Influenza viruses belong to the Orthomyxoviridae family and are classified into three genera of types A, B, and C, which are referred to as influenza A virus, influenza B virus, and influenza C virus, respectively. In general, the influenza virus often refers to the types A and B in particular. Differences among types A, B, and C are based on differences in antigenicity of an M1 protein and an NP protein among proteins which form viral particles. Further, even though the influenza virus is classified into the same types A and B, each of the types is further classified into several subtypes or strains due to a difference in antigenicity of hemagglutinin (hereinafter, also referred to as “HA” simply) which is a molecule on the surface of an envelope or a difference in antigenicity of neuraminidase (NA). Thus, for example, the influenza A virus is further classified into subtypes H1N1, H2N2, H3N2, and the like. The human influenza A virus periodically mutates HA and NA. Thus, vaccination corresponding to the conventional subtype often cannot exert its expected effect.
HA in the influenza A virus is formed of a head region and a stem region which are different in structure, the head region includes a receptor-binding site for the virus to bind to a target cell and is involved in hemagglutination activity of HA, and the stem region includes a fusion peptide required for membrane fusion between the envelope of the virus and an endosome membrane of a cell and is involved in fusion activity (Non Patent Literature 1). Most of anti-HA antibodies, which recognize each of the influenza A virus subtypes H1N1 and H2N2, recognize the head region of HA. However, this region is most frequently mutated. Thus, these antibodies do not react with the subtypes of the human influenza A virus in common, and often lose their recognition abilities along with an antigenic change of HA in the virus.
Patent Literature 1 and Non Patent Literature 2 disclose that a polypeptide was synthesized from the amino acid sequence of the stem region of HA from one type of the influenza A virus subtype H3N2 and an antibody against this polypeptide was acquired. However, a viral neutralization activity was weak in such antibody (Patent Literature 1), and the polypeptide itself used as an antigen exhibited no reactivity with rabbit anti-virus serum obtained by immunization with the subtype H3N2, which was also problematic in antigenicity (Non Patent Literature 2).
If an antibody which is common to the subtypes of the influenza virus, recognizes an antigenic site which is hardly mutated in, for example, the HA or NA molecule, and has a neutralization activity against the influenza virus can be obtained, this can be utilized for diagnosing, preventing, and treating a disease caused by an infection with the virus, and the antigenic site itself becomes useful as a vaccine. There is disclosed an antibody which has a viral neutralization activity against influenza A virus subtypes H1N1 and H2N2 and exhibits no neutralization activity against the subtype H3N2 (Patent Literatures 2 and 3). There is also disclosed an antibody which recognizes a specific polypeptide sequence in the stem region of the influenza A virus subtype H3N2 and does not recognize the subtypes H1N1 and H2N2 (Patent Literature 4). There is also disclosed a human Fab antibody which neutralizes the influenza A virus subtype H3N2 (Patent Literature 5 and Non Patent Literature 3).
In the influenza viruses, the human influenza A virus causes worldwide epidemics and brings many deaths (Patent Literatures 2 to 4). The influenza A virus subtype H3N2 is a subtype which caused worldwide epidemics in the past, and there is a report that a strain resistant to a medicament such as amantadine having an anti-influenza virus action has been increasing in recent years (New York Times, Jan. 15, 2006). However, no report is available for an antibody which effectively exhibits a neutralization activity against a region highly conserved for about 20 years in the influenza A virus subtype H3N2 and in the influenza B virus.